Investigational drugs for the treatment of scleroderma: what's new?

INTRODUCTION: Systemic sclerosis (SSc) is an orphan, chronic, autoimmune, fibrotic disease with unknown etiology characterized by progressive fibrosis of the skin and internal organs. SSc has the highest mortality, the deadliest among the connective tissue diseases, despite the introduction of new treatment options in the past decades. AREAS COVERED: The aim of the current systematic review was to investigate new targeted therapy and their impact on disease progression, mainly focusing on phase I and II clinical trials within the past three years. EXPERT OPINION: Despite recent groundbreaking advancements in understanding SSc pathophysiology, early diagnosis and early introduction of effective targeted treatments within the optimal window of opportunity to prevent irreversible disease damage still represents a significant clinical challenge. Ongoing significant research for new molecular and epigenetics pathways is of fundamental importance to offer new perspectives on disease phenotype and for the development of personalized treatment strategies.

Impaired Fibrinolysis Is Linked With Digital Vasculopathy and Onset of New Digital Ulcers in Systemic Sclerosis.

OBJECTIVE: To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease. METHODS: We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naïve) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored. RESULTS: Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6-0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged (P < 0.001) in patients with new DU episodes, especially those with recurrent DUs. Regression analysis showed that the Raynaud phenomenon visual analog scale and CLT were predictors of new DUs (OR 1.1, 95% CI 1.0-1.1 and OR 1.2, 95% CI 1.1-1.3, respectively). SEM confirmed denser fibrin clots in patients with new DUs. CONCLUSION: Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc.

Microparticles in systemic sclerosis, targets or tools to control fibrosis: This is the question!

Systemic sclerosis is the main systemic fibrotic disease with unknown etiology characterized by peripheral microvascular injury, activation of immune system, and wide-spread progressive fibrosis. Microparticles can be derived from any cell type during normal cellular differentiation, senescence, and apoptosis, and also upon cellular activation. Carrying along a broad range of surface cytoplasmic and nuclear molecules of originating cells, microparticles are closely implicated in inflammation, thrombosis, angiogenesis, and immunopathogenesis. Recently, microparticles have been proposed as biomarkers of endothelial injury, which is the primary event in the genesis of tissue fibrosis. Microparticles may have a role in fostering endothelial to mesenchymal transition, thus giving a significant contribution to the development of myofibroblasts, the most important final effectors responsible for tissue fibrosis and fibroproliferative vasculopathy. Thanks to potent profibrotic mediators, such as transforming growth factor beta, platelet-derived growth factor, high mobility group box 1 protein, nicotinamide adenine dinucleotide phosphate oxidase 4, and antifibrotic agents, such as matrix metalloproteinases, microparticles may play an opposite role in fibrosis.

Disease activity and damage in patients with primary Sjogren's syndrome: Prognostic value of salivary gland ultrasonography.

OBJECTIVES: To assess the association between salivary ultrasonography (sUS) findings and disease activity and damage in patients with primary Sjogren's syndrome (pSS). We investigated the potential prognostic role of sUS as a tool in the assessment of disease activity. METHODS: In 303 pSS patients, disease activity was assessed by the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI), the EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI), the Sjogren's Syndrome Disease Activity Index (SSDAI) and the Sjogren's Syndrome Disease Damage Index (SSDDI). The sUS parenchymal inhomogeneity (de Vita scoring system) was assessed in 303 pSS patients and 111 heathy controls. A receiver operating characteristic (ROC) curve was used to determine the cut-off value of the pathological sUS score. Logistic regression analysis was performed to assess risk factors for moderate and high disease activity. RESULTS: A pathological sUS score ≥ 2 was recorded in 271 (89.7%) patients and 8 (8.6%) healthy controls. Patients with moderate and high ESSDAI and SSDAI scores had significantly higher US activity in comparison to that of pSS patients with low disease activity (p = 0.006; p = 0.01, respectively). Additionally, pSS patients with moderate and high SSDDI scores had higher US activity (p = 0.031). Pathological sUS correlated with the glandular domain within the ESSDAI and SSDDI (p<0.001). The patients with a severe US score (5-6) had a 3.5 times greater chance of having moderate or high disease activity. The specificity of the severe de Vita sUS score for ESSDAI and SSDAI was 85.1% and 85.2%, respectively. In contrast, the sensitivity of a severe de Vita sUS score for ESSDAI was low, at 29.2%, while the sensitivity for the SSDAI was higher, 42.3%. In the analysis of disease activity, a de Vita score ≥ 5 could be used as a risk factor for moderate and high ESSDAI (p = 0.042) and SSDAI (p = 0.006). CONCLUSIONS: Pathological salivary gland ultrasonography is associated with high disease activity and damage in pSS. Consequently, sUS abnormalities might be surrogate items for glandular domains in the assessment of disease activity and damage. Thus, ultrasonography of the salivary gland combined with clinical and serological markers might be part of the next prognostic and therapeutic algorithm in the near future.

The efficacy and safety of autologous conditioned serum (ACS) injections compared with betamethasone and placebo injections in the treatment of chronic shoulder joint pain due to supraspinatus tendinopathy: a prospective, randomized, double-blind, controlled study.

AIMS: Autologous conditioned serum (ACS; marketed as Orthokine®) is an autologous blood product that has previously shown efficacy in treatment of joint osteoarthritis, spinal radiculopathy, tendon and muscle injuries in randomized controlled trials. In this 24-week, randomized, double-blind study, we compared the efficacy and safety of ACS with glucocorticoid (betamethasone) injections in chronic supraspinatus tendinopathy patients. MATERIAL AND METHODS: Thirty-two patients with chronic supraspinatus tendinopathy were enrolled in the study. The ACS group received four ACS injections once weekly over four weeks and the glucocorticoid group received three betamethasone injections once weekly over three weeks with a placebo (saline) injection at week 4 into the enthesis and paratenon of the supraspinatus tendon. Study endpoints were pain intensity (VAS) and Constant Shoulder Score (CSS) assessed at weeks 0, 4 and 24. RESULTS: Shoulder pain intensity improved after 4 weeks and significantly improved after 24 weeks in patients treated with ACS compared with those treated with glucocorticoids (pain intensity week 4: ACS=22.0, glucocorticoid=32.0; week 24: ACS=15.0, glucocorticoid=40.0). CSS improved to a similar extent in both groups after 4 weeks. After 24 weeks, ACS patients exhibited significantly greater CSS improvements than glucocorticoid patients. Adverse events (n=8) were reported in betamethasone patients. CONCLUSIONS: Compared with betamethasone, ACS therapy improved joint function and reduced shoulder pain more effectively after 4 weeks of treatment; these improvements were sustained to week 24. Combined with its favorable safety profile, ACS appears to be a more effective treatment than glucocorticoids and could enhance the quality of life in patients with chronic rotator cuff tendinopathy.